CHEM 231: Organic Form and Function
CHEM 231: Organic Form and Function
Laboratory 4 Nucleophilic Substitution Specific Practical Goals
to prepare a substance using unimolecular nucleophilic substitution to isolate a product using vacuum filtration to estimate the purity of a compound using TLC to characterize a product using melting point determination
Background The 1,1,4,4-tetramethyltetralin substructure is featured in several retinoic acid mimics useful for anti-cancer 1 therapies. For example, Tamibarotene (Amnolake, 1) and Bexarotene (Targretin, 2) are approved pharmaceuticals for the treatment of acute promyelocytic leukaemia (APL) and cutaneous T cell lymphoma (CTCL), respectively, and the newly developed indole derivative 3 has shown promising activity against liver, breast and colon cancer cell 2 lines.
Figure 1. Some pharmaceutically active tetramethyltetralin derivatives (with the diisobutyl moiety highlighted) One of the most convenient methods for constructing tetramethyltetralins is the fusion of a diisobutyl moiety onto an existing benzene ring (as shown in Scheme 1) using a Friedel-Crafts reaction (which will be covered in the second semester). In this case, the source of the diisobutyl moiety is 2,5-dichloro-2,5-dimethyl-hexane (4). The requisite dichloride 4 is commercially available, although it is expensive at $252/g. However, it can be easily prepared from the readily available 2,5-dimethyl2,5-hexanediol 7 (11¢/g) by treatment with concentrated hydrochloric acid (Scheme 2). The starting material, which is a solid (mp 86-90°C), dissolves in the hydrochloric acid Scheme 1. A route to tetramethyltetralins medium, but then the much less polar product—also a solid (mp 63-64°C)—precipitates out as it is formed, allowing for convenient isolation by vacuum filtration. The reaction proceeds through an SN1 mechanism, in which the alcohol functionality is initially protonated by the strong acid. Water (a good leaving group) is lost, forming a stable tertiary carbocation, which is captured by chloride. The process is repeated for the remaining alcohol functionality.
Scheme 2. Preparation of 2,5-dichloro-2,5-dimethylhexane 1
Boehm, M.F.; Zhang, L.; Badea, B.A.; White, S.K.; Mais, D.E.; Berger, E.; Suto, C.M.; Goldman, M.E.; Heyman, R.A.S., J. Med. Chem. 1994, 37, 293. 2 Gurkan-Alp, A.S.; Mumcuoglu, M.; Andac, C.A.; Dayanc, E.; Cetin-Atalay, R.; Buyukbingol, E., Eur. J. Med. Chem. 2012, 58, 346.
Pre-lab Reading Technique Primers 1 & 2: TLC & Filtration Safety Considerations You must abide by all laboratory safety rules. 2,5-Dimethyl-2,5-hexanediol [110-03-2]. Not classified as a hazardous substance. Normal precautions should be taken when handing. Hydrochloric acid, 37% [7647-01-0]. May be corrosive to metals. Causes severe skin burns and eye damage. May cause respiratory irritation. 2,5-Dichloro-2,5-dimethylhexane [6223-78-5]. Not classified as a hazardous substance. Normal precautions should be taken when handing. Procedural Overview
3
Important Note: You will be evaluated on the amount of compound you recover. Therefore, make sure all transfers are quantitative. Likewise, purity counts, so make sure all glassware is clean before using. Weigh 1.7 mmol 2,5-dimethyl-2,5-hexanediol into a 25 mL Erlenmeyer flask and add 2.0 mL hydrochloric acid, 37%. Swirl the flask vigorously for 10 min, taking care not to splash any of the contents out of the flask. Collect the resulting solid by vacuum filtration, using deionized water to rinse the product forward. Leave the vacuum running for about 10 min to dry the filtercake, and then carefully collect and weigh the solids. After the yield has been determined, analyze the product by TLC vs. the starting material using 80% ethyl acetate in hexane as the mobile phase. Visualize the spots by dipping into permanganate solution. Finally, take a melting point of the product. revision 8-27-14
3
Adapted from: Wagner & Marshall, J. Chem. Educ. 2010, 87, 81.
Laboratory 4 Nucleophilic Substitution Specific Practical Goals
to prepare a substance using unimolecular nucleophilic substitution to isolate a product using vacuum filtration to estimate the purity of a compound using TLC to characterize a product using melting point determination
Background The 1,1,4,4-tetramethyltetralin substructure is featured in several retinoic acid mimics useful for anti-cancer 1 therapies. For example, Tamibarotene (Amnolake, 1) and Bexarotene (Targretin, 2) are approved pharmaceuticals for the treatment of acute promyelocytic leukaemia (APL) and cutaneous T cell lymphoma (CTCL), respectively, and the newly developed indole derivative 3 has shown promising activity against liver, breast and colon cancer cell 2 lines.
Figure 1. Some pharmaceutically active tetramethyltetralin derivatives (with the diisobutyl moiety highlighted) One of the most convenient methods for constructing tetramethyltetralins is the fusion of a diisobutyl moiety onto an existing benzene ring (as shown in Scheme 1) using a Friedel-Crafts reaction (which will be covered in the second semester). In this case, the source of the diisobutyl moiety is 2,5-dichloro-2,5-dimethyl-hexane (4). The requisite dichloride 4 is commercially available, although it is expensive at $252/g. However, it can be easily prepared from the readily available 2,5-dimethyl2,5-hexanediol 7 (11¢/g) by treatment with concentrated hydrochloric acid (Scheme 2). The starting material, which is a solid (mp 86-90°C), dissolves in the hydrochloric acid Scheme 1. A route to tetramethyltetralins medium, but then the much less polar product—also a solid (mp 63-64°C)—precipitates out as it is formed, allowing for convenient isolation by vacuum filtration. The reaction proceeds through an SN1 mechanism, in which the alcohol functionality is initially protonated by the strong acid. Water (a good leaving group) is lost, forming a stable tertiary carbocation, which is captured by chloride. The process is repeated for the remaining alcohol functionality.
Scheme 2. Preparation of 2,5-dichloro-2,5-dimethylhexane 1
Boehm, M.F.; Zhang, L.; Badea, B.A.; White, S.K.; Mais, D.E.; Berger, E.; Suto, C.M.; Goldman, M.E.; Heyman, R.A.S., J. Med. Chem. 1994, 37, 293. 2 Gurkan-Alp, A.S.; Mumcuoglu, M.; Andac, C.A.; Dayanc, E.; Cetin-Atalay, R.; Buyukbingol, E., Eur. J. Med. Chem. 2012, 58, 346.
Pre-lab Reading Technique Primers 1 & 2: TLC & Filtration Safety Considerations You must abide by all laboratory safety rules. 2,5-Dimethyl-2,5-hexanediol [110-03-2]. Not classified as a hazardous substance. Normal precautions should be taken when handing. Hydrochloric acid, 37% [7647-01-0]. May be corrosive to metals. Causes severe skin burns and eye damage. May cause respiratory irritation. 2,5-Dichloro-2,5-dimethylhexane [6223-78-5]. Not classified as a hazardous substance. Normal precautions should be taken when handing. Procedural Overview
3
Important Note: You will be evaluated on the amount of compound you recover. Therefore, make sure all transfers are quantitative. Likewise, purity counts, so make sure all glassware is clean before using. Weigh 1.7 mmol 2,5-dimethyl-2,5-hexanediol into a 25 mL Erlenmeyer flask and add 2.0 mL hydrochloric acid, 37%. Swirl the flask vigorously for 10 min, taking care not to splash any of the contents out of the flask. Collect the resulting solid by vacuum filtration, using deionized water to rinse the product forward. Leave the vacuum running for about 10 min to dry the filtercake, and then carefully collect and weigh the solids. After the yield has been determined, analyze the product by TLC vs. the starting material using 80% ethyl acetate in hexane as the mobile phase. Visualize the spots by dipping into permanganate solution. Finally, take a melting point of the product. revision 8-27-14
3
Adapted from: Wagner & Marshall, J. Chem. Educ. 2010, 87, 81.
